EP0003230A2 - Process for the preparation of o-phthalic aldehydes optionally having several substituents - Google Patents

Abstract

The present invention relates to a process for the preparation of optionally substituted o-phthalaldehydes by hydrolysis of α, α, α ', α'-tetrahalogen-o-xylenes with a carboxylate in an aqueous medium in the presence of a phase transfer catalyst and an organic base.

Description

Processes for the preparation of o-phthalaldehyde have long been described in the literature in a number of ways.

Worth mentioning is the oxidation process in several stages by J. Thiele and E. Winter, A 311, 360 (1900), which proceeds from o-xylene via phthalaldehyde tetraacetate. The method described by F. Weygand and D. Tietjen in B 84, 625 (1951) provides the o-phthalaldehyde, whereby N, N, N ', N'-tetramethyl-o-phthalamide is reduced by means of lithium aluminum hydride as a suitable carboxylic acid derivative. A reduction in the tetramethyl-o-phthalamide used can only be carried out with the most embarrassing exclusion of moisture, so that considerable procedural difficulties have to be accepted. Another method according to F. Weygand, KG Kinkel and D. Tietjen in B 83, 394 (1950) starts from o-phthalic alcohol. The alcohol is oxidized with selenium dioxide, whereby the ester of selenic acid forms as an intermediate product, which is only converted to aldehyde by careful heating over an open flame. So far, the one described by J. Thiele and 0. Günther, A 347, 106 (1906) has been of interest Hydrolysis of α, α, α ', α'-tetrabromo-o-xylene using potassium oxalate. The long reaction time and the absolutely necessary use of a solution mixture of alcohol and water in relatively large volumes proved to be disadvantageous. The hydrolysis of tetrabromo-o-xylene described by F. Weygand et al., B 80, 391 (1947) can also be described as an interesting method. However, the use of fuming sulfuric acid proves to be disadvantageous here. The large volume of sulfuric acid aqueous solution obtained by pouring it onto ice must be saturated with large amounts of sodium chloride and shaken out with large volumes of ethyl acetate. Although o-phthalaldehyde has long been one of the known substances, a simple synthesis, ie, using inexpensive starting materials and reagents and using little steps, is still missing to prepare this compound, which gives it in good yield.

The invention relates to a particularly advantageous process for the preparation of optionally substituted o-phthalaldehydes.

in der R₁ und R₂ unabhängig voneinander Wasserstoff, Niederalkyl, Hydroxy, Halogen, Nitro, Cyano oder Carboxy bedeuten, besteht darin, dass man ein gegebenenfalls substituiertes α,α,α',α'-Tetrahalogen-o-xylol der Formel II,

in der R₁ und R₂ die oben angegebene Bedeutung haben und X ein Halogenatom bedeutet mit einem Carboxylat in wässrigem Medium in Gegenwart eines Phasentransferkatalysators und einer anorganischen Base zum gegebenenfalls substituierten o-Phthalaldehyd hydrolysiert.The process according to the invention for the preparation of an optionally substituted o-phthalaldehyde of the formula I,

in which R ₁ and R ₂ independently of one another are hydrogen, lower alkyl, hydroxy, halogen, nitro, cyano or carboxy mean that an optionally substituted α, α, α ', α'-tetrahalo-o-xylene of the formula II,

in which R ₁ and R _{2 have} the meaning given above and X denotes a halogen atom with a carboxylate in aqueous medium in the presence of a phase transfer catalyst and an inorganic base to hydrolyze the optionally substituted o-phthalaldehyde.

If R ₁ and / or R ₂ are lower alkyl, they can be a straight or branched lower alkyl radical having 1-7 carbon atoms and are preferably methyl, ethyl, n-propyl and isopropyl, furthermore n-butyl, isobutyl, sec. Butyl, tert. Butyl, n-amyl, isoamyl, n-hexyl, isohexyl or n-heptyl.

If R ₁ and R _{2 represent} a halogen atom, halogen atoms up to atom number 35, such as fluorine, chlorine or bromine, are suitable. Chlorine or bromine are preferably suitable as the substituent X of the starting compound II.

Carboxylate is understood to mean the salt of an organic carboxylic acid, the salts being primarily metal, such as alkali metal or alkaline earth metal salts, furthermore ammonium salts of such acids, in particular of corresponding aliphatic, and also also aromatic carboxylic acids, such as of lower alkane carboxylic acids, for example of formic, Acetic or propionic acid, as well as benzoic acid. It is preferred to use alkali metal, such as sodium or potassium, and also calcium lower alkanoates with 1 to 3 carbon atoms, including the formates, in particular the corresponding formates and acetates, and primarily Sodium or potassium formate or acetate.

The phase transfer catalyst used is predominantly onium salts, in particular quaternary ammonium salts and phosphonium salts, for example tetraalkylammonium salts or phosphonium salts, in particular corresponding halides, such as tetra-n-butylammonium chloride or bromide or tetra-n-butylphosphonium chloride or bromide or ethyl bromide or ethyl bromide or ethyl bromide or ethyl bromide or ethyl bromide or ethyl bromide or ethyl bromide or ethyl bromide, ethyl trio or aryl-lower alkyl-tri-lower alkyl ammonium salts, in particular corresponding halides, for example Benzyltriethylammonium chloride. The corresponding arsonium and sulfonium salts (E.V. Dehmlow, Ang. Chem. 89/8, 521-533) can also be used in an analogous manner.

A base is added to neutralize the acid corresponding to the carboxylate reagent which is formed in the hydrolysis of acylal intermediates and to accelerate this hydrolysis. Inorganic bases, such as corresponding metallic bases, e.g. Alkali metal or alkaline earth metal bases, in particular the corresponding hydroxides, hydrogen carbonates or preferably carbonates, such as sodium or potassium hydroxide or hydrogen carbonate, and preferably potassium or primarily sodium carbonate. The corresponding hydroxides, bicarbonate and carbonates of calcium or magnesium can be used in an analogous manner, calcium carbonate possibly being preferred as the poorly soluble base.

The reaction is usually carried out in a two-phase system, which consists of an aqueous and an organic phase, the latter from the α, α, α ', α'-tetrahslogene-o-xylene, for example from the a, a, α'α '-Tetrabromo- or α, α, α', α'-tetrachloro-x-xylene is formed. The amounts of the carboxylate and phases to be used according to the invention Transfer catalyst compounds can vary considerably. An inorganic base is added to the reaction mixture to neutralize the resulting acid, which converts it back into the carboxylate compound. In theory, one could use catalytic amounts, ie less than equimolar amounts, for example from about 1 mole percent to about 50 mole percent (based on the starting material) of both the carboxylate and the phase transfer compound. The latter are usually added in catalytic amounts, for example from about 1 mole percent to about 30 mole percent (based on the starting material), it also being possible to use equimolar amounts or an excess of the phase transfer catalyst. The carboxylate compound is usually used in approximately equimolar amounts, if appropriate in a lower and preferably in an excess. A readily soluble base, such as an alkali metal carbonate, for example sodium carbonate, is preferably added in the course of the reaction, usually in portions. If necessary, the reaction mixture is temporarily cooled before adding the base, for example in order to prevent foaming when using a carbonate or bicarbonate. However, a poorly soluble base can also be present in the reaction mixture right from the start, which is why it is also preferably used, for example calcium carbonate.

The hydrolysis is carried out using a readily soluble base, for example an alkali metal base, preferably in a pH range from about 7.5 to about 11 and in the presence of a poorly soluble base, for example an alkaline earth metal carbonate, such as calcium carbonate, in a pH range below 7.5 executed; depending on the solubility of the alkaline earth carbonate used, the pH drops to about 4.
Since the α, α, α ', α'-tetrabromo-o-xylene or α, α, α', α'-tetrachloro-x-xylene as the starting material. In the molten state forms the organic phase of the two-phase system, the reaction becomes preferably at a temperature above 60 ° C, for example at a temperature of about 65 ° C to about 160 ° C, preferably from 90 ° C to about 140 ° C, further under normal pressure or elevated pressure, for example in a bomb tube or autoclave, and / or carried out under an inert gas atmosphere, for example nitrogen or argon.

The optionally substituted α, α, α ', α'-tetrabromo or α, α, α', α'-tetrachloro-xylenes used as starting material are known and can e.g. by treating o-xylenes with elemental bromine while irradiating them with UV light (Organic Syntheses, Coll. Vol. IV, p. 807-808) or by treating o-xylenes with elemental chlorine while irradiating them with visible light (Houben-Weyl , Vol. 5/3, p. 739).

Compared to the closest prior art, i.e. compared to the process described by F. Weygand et al., B 80, 391 (1947), the hydrolysis is carried out without fuming sulfuric acid. The resulting large amount of aqueous solution saturated with common salt must in turn be shaken out with a large volume of ethyl acetate as the solvent. These procedural disadvantages do not exist in the method which can be carried out according to the invention.

The o-phthalaldehyde or optionally substituted o-phthalaldehyde which can be prepared according to the invention are used, for example, as a reagent for the qualitative and quantitative determination of ammonia or else primary amines (peptide chemistry). Secondary amines do not react with the o-phthalaldehydes.

· In the following examples, the temperatures are given in degrees Celsius.

example 1

A suspension consisting of 10.0 g α, α, α ', α'-tetrabromo-o-xylene (23.7 mmol), 9.7 g sodium acetate (118 mmol), 1.74 g tetrabutylammonium bromide (5.4 mmol ), 4.75 g of calcium carbonate and 10 ml of distilled water is heated to reflux in a nitrogen atmosphere with vigorous stirring, the internal temperature adjusting to 118 °. After a reaction time of 6 hours, the reaction mixture is allowed to cool, 50 ml of ethyl acetate are added and the mixture is filtered. The organic phase is separated off in a separating funnel and the aqueous phase is washed again with ethyl acetate. The combined organic extracts (ethyl acetate extracts) are washed with a saline solution, dried over magnesium sulfate and then concentrated in vacuo. The residue obtained is taken up in 40 ml of toluene and the solution is chromatographically purified on a column filled with silica gel (100 g). After evaporation of the eluate from toluene, 2.10 g (66.2% of theory) o -Phthalaldehyde, FP 53-55 °, can be isolated.

Example 2

A suspension consisting of 10.0 g of α, α, α ', α'-tetrabromo-o-xylene. 8.0 g of sodium formate, 1.74 g of tetrabutylammonium bromide, 4.75 g of calcium carbonate and 10 ml of distilled water are refluxed in a nitrogen atmosphere with vigorous stirring for 9 hours. After cooling, 50 ml of ethyl acetate are added. and the reaction mixture processed as in Example 1. After chromatographic purification (100 g silica gel in the column), 2.54 g o-phthalaldehyde (80.2% of theory), F.P. 53-55 °, isolated.

Example 3

Analogously to Example 1, a suspension consisting of 5.78 g of α, α, α ', α'-tetrachloroxylene (purity approx. 95%), 9.62 g of sodium acetate, 1.74 g of tetrabutylammonium bromide, 4.75 g of calcium carbonate and 10 ml of water are placed in a nitrogen atmosphere Stir cooked under reflux for 29 hours. After cooling, the mixture is diluted with water, extracted twice with ethyl acetate (100 ml each), the combined organic layers are washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off in vacuo and the crystalline residue is dissolved in toluene and chromatographed on 100 g of silica gel. o-Phthalaldehyde is eluted with toluene ethyl acetate = 19: 1, whereby after evaporation of the eluate 2.30 g (72% of theory) of purified o-phthalaldehyde are obtained.

Claims (11)

1. Process for the preparation of an optionally substituted o-phthalaldehyde of the formula I,

in which R ₁ and R _{2 are} independently hydrogen, lower alkyl, hydroxy, halogen, nitro, cyano or carboxy, characterized in that an optionally substituted α, α, α ', α'-tetrahalo-o-xylene of the formula II ,

in which R ₁ and R _{2 have} the meaning given above and X denotes a halogen atom with a carboxylate in aqueous medium in the presence of a phase transfer catalyst and an organic base. 2. The method according to claim 1, characterized in that one carries out the hydrolysis in the presence of a quaternary ammonium salt or phosphonium salt as a phase transfer catalyst and a metallic base, with an alkali metal, alkaline earth metal or ammonium salt of an organic acid. 3. The method according to claim 1 or 2, characterized in that one carries out the hydrolysis in the presence of a tetraniederalkylammoniunsalzes and an alkali metal or alkaline earth metal base with an alkali, alkaline earth or ammonium salt of an aliphatic carboxylic acid, such as a lower alkane carboxylic acid or an aromatic carboxylic acid. 4. The method according to any one of claims 1 to 3, characterized in that one carries out the hydrolysis in the presence of tetra-n-butylammonium chloride or bromide as phase transfer catalyst and an alkali metal or alkaline earth metal carbonate with an alkali metal or alkaline earth metal formate or acetate. 5. The method according to claim 1 or 2, characterized in that one carries out the hydrolysis in the presence of benzyltriethylammonium chloride or bromide and an alkali metal or alkaline earth metal carbonate with an alkali metal or alkaline earth metal formate or acetate. 6. The method according to any one of claims 1 to 4, characterized in that one carries out the hydrolysis in the presence of tetra-n-butylammonium chloride or bromide and calcium carbonate with sodium formate or acetate. 7. The method according to any one of claims 1 to 6, characterized in that one works in the absence of an organic solvent at a temperature above 60 °. 8. The method according to any one of claims 1 to 7, characterized in that an optionally substituted a, a, a ', a'- as optionally substituted a, a, a', a'-tetrahalo-o-xylene of the formula II Tetrabromo or α, α, α ', α'-tetrachloro-xylene used. 9. The procedure described in Examples 1 to 3. 10. The compounds obtainable by the process of claims 1 to 8. 11. The compounds obtainable by the process of Examples 1 to 3.